The brain is estimated to be made up of one hundred billion neurons which are connected by 100 trillion synapses. Synapses are the major way in which neurons communicate and therefore form the biological basis for brain function and behavior. Synapses are dynamic and changes in their structure, function and number (collectively termed plasticity) occur during learning, mediate memories, and sculpt the development of our sensory experiences. Understanding how synaptic plasticity occurs and how stable synaptic properties maintain memories throughout a lifetime is an ultimate goal in neuroscience.
One major focus of the Huber lab is to understand the cellular and molecular mechanisms which mediate synaptic plasticity. A major mechanism by which synaptic plasticity occurs is through the localized and synaptic synthesis of new proteins. Much of our work is focused on studying a form of synaptic weakening or depression which relies on very rapid, protein synthesis at synapses. Long-term synaptic depression or LTD is induced by activation of Gq coupled receptors, such as the metabotropic glutamate receptors (mGluRs). By studying the mechanisms mGluR-dependent LTD, we can address major research questions such as: How does synaptic activity regulate rapid protein synthesis at synapses? What are the proteins which are synthesized and how do they affect synapse function? What role does synaptic or dendritic protein synthesis play in the nervous system and how do alterations or dysfunction of the dendritic protein synthesis machinery contribute to neurological disease?
Altered synapse structure and dysfunction is thought to be the origin of many neurological diseases. Motivated by our basic research findings, we discovered altered synaptic plasticity and function in the mouse model of mental retardation and autism, Fragile X Syndrome. Therefore, another aim of the lab is to identify and understand how alterations in synaptic function and connectivity lead to mental retardation and autism. Specifically, we find that LTD is enhanced and abnormally regulated in a mouse model of human mental retardation, Fragile X Syndrome. Fragile X Syndrome is caused by loss of function mutations in an RNA binding protein called Fragile X Mental Retardation Protein (FMRP) which is an RNA binding protein and regulates protein synthesis at synapses. A third goal of my lab is to determine how RNA binding proteins, such as FMRP, regulate dendritic protein synthesis and, in turn, synapse function.
To address these research questions we use a multi-disciplinary approach including electrophysiology, imaging, and biochemical methods in the hippocampus and neocortex, major brain structures implicated in human cognition. Work is our laboratory is supported by grants from the NIH-NINDS, the FRAXA Research and Autism Speaks Foundations.
RESEARCH INTERESTS
Synapse function and plasticity
Mental Retardation/ Autism/Fragile X Syndrome
G coupled neurotransmitter receptor signaling
Inhibitory neuron function
Electrophysiology
RECENT PUBLICATIONS
Gallagher, S.M.. Daly, C.A., Bear, M.F. and Huber, K.M., "Extracellular signal-regulated protein kinase activation is required for metabotropic glutamate receptor -dependent long-term depression in hippocampal area CA1" Journal of Neuroscience, 24(20):4859-64, May 2004
Nosyreva, E.N. and Huber, K.M., "Developmental switch in mechanisms of hippocampal metabotropic glutamate receptor dependent synaptic plasticity" Journal of Neuroscience, 25(11)::2992-3001, March 2005
Volk, L, Daly, C.A. and Huber K.M., "Differential roles for group 1 mGluR subtypes in induction and expression of chemically-induced hippocampal long-term depression" Journal of Neurophysiology, 95(4):2427-38, January 2006
Nosyreva E. N. and Huber K.M., "Metabotropic glutamate receptor dependent long-term depression persists in the absence of protein synthesis in the mouse model of Fragile X Syndrome" Journal of Neurophysiology, 95(5)::3291-5, February 2006
Pfeiffer, B.E. and Huber, K.M., "Fragile X Mental Retardation Protein induces synapse loss through acute postsynaptic translational regulation" Journal of Neuroscience, 27(12):3120-30, March 2007
SIGNIFICANT PUBLICATIONS
Huber, K.M., Kayser, M.S. and M.F. Bear, "Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent LTD" Science, 288(5469):1254-1257, May 2000
Huber, K.M., Gallagher, S., Warren, S.T. and Bear, M.F., "Altered synaptic plasticity in a mouse model of fragile X mental retardation." Proc. Natl. Acad. Sci., 99(11):7746-7750, April 2002
Pfeiffer, B.E. and Huber, K.M., "Fragile X Mental Retardation Protein induces synapse loss through acute postsynaptic translational regulation" Journal of Neuroscience, 27(12):3120-30, March 2007
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